U.S. patent application number 10/007272 was filed with the patent office on 2002-11-28 for novel crystalline forms of an antiviral benzimidazole compound.
Invention is credited to Glover, Bobby Neal, Huang, Lian-Feng, Lancaster, Robert William, Long, Stacey Todd, Rizzolio, Michele Catherine, Schmitt, Eric Allen, Sickles, Barry Riddle.
Application Number | 20020177703 10/007272 |
Document ID | / |
Family ID | 10829932 |
Filed Date | 2002-11-28 |
United States Patent
Application |
20020177703 |
Kind Code |
A1 |
Glover, Bobby Neal ; et
al. |
November 28, 2002 |
Novel crystalline forms of an antiviral benzimidazole compound
Abstract
The invention relates to Form physical forms of
5,6-dichloro-2-(isopropyla-
mino)-1-.beta.-L-ribofuranosyl-1H-benzimidazole, pharmaceutical
compositions comprising the same, and their use in medical
therapy.
Inventors: |
Glover, Bobby Neal; (Durham,
NC) ; Huang, Lian-Feng; (Durham, NC) ;
Lancaster, Robert William; (Stevenage, GB) ; Long,
Stacey Todd; (Durham, NC) ; Rizzolio, Michele
Catherine; (Durham, NC) ; Schmitt, Eric Allen;
(Libertyville, IL) ; Sickles, Barry Riddle;
(Durham, NC) |
Correspondence
Address: |
DAVID J LEVY, CORPORATE INTELLECTUAL PROPERTY
GLAXOSMITHKLINE
FIVE MOORE DR.
PO BOX 13398
DURHAM
NC
27709-3398
US
|
Family ID: |
10829932 |
Appl. No.: |
10/007272 |
Filed: |
October 29, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10007272 |
Oct 29, 2001 |
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09647962 |
Oct 6, 2000 |
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09647962 |
Oct 6, 2000 |
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PCT/EP99/02214 |
Apr 1, 1999 |
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Current U.S.
Class: |
536/28.9 |
Current CPC
Class: |
C07H 19/052 20130101;
A61K 31/7056 20130101; A61P 31/22 20180101; C07D 405/04 20130101;
C07B 2200/13 20130101; A61K 31/4184 20130101; A61P 31/12
20180101 |
Class at
Publication: |
536/28.9 |
International
Class: |
C07H 019/04 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 7, 1998 |
GB |
9807354.7 |
Claims
1. Form II
5,6,-dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-be-
nzimidazole having substantially the same X-ray powder diffraction
pattern as FIG. 2, wherein said X-ray powder diffraction pattern is
obtained with a diffractometer equipped with a diffracted beam
curved graphite monochromator using copper K.alpha.
X-radiation.
2. A crystalline form of
5,6,-dichloro-2-(isopropylamino)-1-.beta.-L-ribof-
uranosyl-1H-benzimidazole characterized by an X-ray powder
diffraction pattern expressed in terms of 2 theta angles and
obtained with a diffractometer equipped with a diffracted beam
curved graphite monochromator using copper K.alpha. X-radiation,
wherein said X-ray powder diffraction pattern comprises 2 theta
angles at five or more positions selected from the group consisting
of at five or more of the following positions: 7.91.+-.0.09,
17.33.+-.0.09, 18.23.+-.0.95, 19.60.+-.0.09, 21.88.+-.0.09,
23.24.+-.0.09, 23.92.+-.0.09, 25.27.+-.0.09, 27.70.+-.0.09, and
29.21.+-.0.09 degrees.
3.
5,6,-Dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-benzimidaz-
ole ethanol solvate having substantially the same X-ray powder
diffraction pattern as FIG. 3, wherein said X-ray powder
diffraction pattern is obtained with a diffractometer equipped with
a diffracted beam curved graphite monochromator using copper
K.alpha. X-radiation.
4. Ethanol solvate of
5,6,-dichloro-2-(isopropylamino)-1-.beta.-L-ribofura-
nosyl-1H-benzimidazole characterized by an X-ray powder diffraction
pattern expressed in terms of 2 theta angles and obtained with a
diffractometer equipped with a diffracted beam curved graphite
monochromator using copper K.alpha. X-radiation, wherein said X-ray
powder diffraction pattern comprises 2 theta angles at five or more
positions selected from the group consisting of at five or more of
the following positions: 9.07.+-.0.05, 10.38.+-.0.05,
15.95.+-.0.05, 17.72.+-.0.05, 20.75.+-.0.05, 21.37.+-.0.05,
22.96.+-.0.05, 23.93.+-.0.05, 25.40.+-.0.05, and 29.05.+-.0.05
degrees.
5. Form V
5,6,-dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-ben-
zimidazole having substantially the same X-ray powder diffraction
pattern as FIG. 5, wherein said X-ray powder diffraction pattern is
obtained with a diffractometer equipped with a diffracted beam
curved graphite monochromator using copper K.alpha.
X-radiation.
6. A crystalline form of
5,6,-dichloro-2-(isopropylamino)-1-.beta.-L-ribof-
uranosyl-1H-benzimidazole characterized by an X-ray powder
diffraction pattern expressed in terms of 2 theta angles and
obtained with a diffractometer equipped with a diffracted beam
curved graphite monochromator using copper K.alpha. X-radiation,
wherein said X-ray powder diffraction pattern comprises 2 theta
angles at five or more positions selected from the group consisting
of at five or more of the following positions: 13.30.+-.0.05,
18.13.+-.0.05, 18.78.+-.0.05, 20.41.+-.0.05, 21.75.+-.0.05,
23.02.+-.0.05, 26.87.+-.0.05, 28.34.+-.0.05, 28.55.+-.0.05, and
30.22.+-.0.05 degrees.
7. A composition comprising an admixture of two or more forms or
solvates of
5,6,-dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-benzimida-
zole according to any of claims 1-6.
8. A composition comprising Form II
5,6,-dichloro-2-(isopropylamino)-1-.be-
ta.-L-ribofuranosyl-1H-benzimidazole according to claim 1 and
amorphous
5,6,-dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-benzimidazol-
e.
9. A composition comprising Form I
5,6,-dichloro-2-(isopropylamino)-1-.bet-
a.-L-ribofuranosyl-1H-benzimidazole having substantially the same
X-ray powder diffraction pattern as FIG. 1 and Form V
5,6,-dichloro-2-(isopropy-
lamino)-1-.beta.-L-ribofuranosyl-1H-benzimidazole having
substantially the same X-ray powder diffraction pattern as FIG. 5,
wherein said X-ray powder diffraction patterns are obtained with a
diffractometer equipped with a diffracted beam curved graphite
monochromator using copper K.alpha. X-radiation.
10. The composition according to claim 9, further comprising Form
IV
5,6,-dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-benzimidazol-
e characterized by the X-ray powder diffraction pattern expressed
in terms of 2 theta angles and obtained with a diffractometer
equipped with a diffracted beam curved graphite monochromator using
copper K.alpha. X-radiation, wherein said X-ray powder diffraction
pattern comprises 2 theta angles at five or more positions selected
from the group consisting of at five or more of the following
positions: 9.29.+-.0.05, 16.04.+-.0.05, 18.67.+-.0.05,
22.06.+-.0.05, 22.68.+-.0.05, 23.34.+-.0.05, 24.40.+-.0.05,
29.64.+-.0.05, 30.92.+-.0.05, and 31.62.+-.0.05 degrees.
11. A pharmaceutical composition comprising a compound as claimed
in any one of claims 1 to 6 and at least one pharmaceutically
acceptable carrier therefor.
12.
5,6,-Dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-benzimida-
zole as claimed in any one of claims 1-6 for use in medical
therapy.
13. Use of
5,6,-dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-be-
nzimidazole as claimed in any one of claims 1 to 6 in the
preparation of a medicament for the treatment of a viral
infection.
14. A method for the treatment of a viral infection a human which
comprises administering to the human host, an effective antiviral
amount of a solvate or crystalline form of
5,6,-dichloro-2-(isopropylamino)-1-.b-
eta.-L-ribofuranosyl-1H-benzimidazole as claimed in any one of
claims 1 to 6.
15. A process for the production of
5,6,-dichloro-2-(isopropylamino)-1-.be-
ta.-L-ribofuranosyl-1H-benzimidazole in an anhydrous crystalline
form said process comprising the steps of: a) providing
5,6,-dichloro-2-(isopropyla-
mino)-1-.beta.-L-ribofuranosyl-1H-benzimidazole in solution either
in free base or salt form; b) isolating
5,6,-dichloro-2-(isopropylamino)-1-.beta.-
-L-ribofuranosyl-1H-benzimidazole from the solution and optionally
removing unbound solvent leaving the
5,6,-dichloro-2-(isopropylamino)-1-.-
beta.-L-ribofuranosyl-1H-benzimidazole in substantially dry form;
c) treating
5,6,-dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-ben-
zimidazole with a solubilising solvent serving to convert an amount
of said optionally dried
5,6,-dichloro-2-(isopropylamino)-1-.beta.-L-ribofur-
anosyl-1H-benzimidazole into said
5,6,-dichloro-2-(isopropylamino)-1-.beta-
.-L-ribofuranosyl-1H-benzimidazole anhydrous crystalline form; and
d) isolating said anhydrous crystalline form.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to anhydrous crystalline forms
and solvates of the antiviral compound
5,6-dichloro-2-(isopropylamino)-1-(.be-
ta.-L-ribofuranosyl)-1H-benzimidazole (also known as 1263W94; a
compound of formula (I)), pharmaceutical formulations comprising
anhydrous crystalline forms and solvates of this compound, and
their use in therapy.
[0002]
5,6-Dichloro-2-(isopropylamino)-1-(.beta.-L-ribofuranosyl)-1H-benzi-
midazole (1263W94) is a benzimidazole derivative useful in medical
therapy. WO96/01833 discloses
5,6-dichloro-2-(isopropylamino)-1-(.beta.-L-
-ribofuranosyl)-1H-benzimidazole and its use for the treatment or
prophylaxis of viral infections such as those caused by herpes
viruses. The compound as disclosed in WO96/01833 is an amorphous,
non-crystalline, hygroscopic material.
[0003] The structure of
5,6-dichloro-2-(isopropylamino)-1-(.beta.-L-ribofu-
ranosyl)-1H-benzimidazole, a compound of formula (I) is shown
below: 1
[0004] We have now found that the compound of formula (I) may be
prepared in novel crystalline forms and solvates. The novel
crystalline forms and solvates of the present invention are more
thermodynamically stable than the amorphous form disclosed in
WO96/01833. The novel crystalline forms and solvates have the
further advantage that they are essentially non-hygroscopic. These
crystalline forms and solvates have good storage properties and can
be readily formulated into pharmaceutical compositions such as
tablets, capsules, and liquid systems. The crystalline forms and
solvates may be characterized by their X-ray powder diffraction
patterns.
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] FIG. 1. X-ray powder diffraction pattern of Form I of the
compound of formula (I). This pattern was obtained in accordance
with the procedures set forth in Example 18.
[0006] FIG. 2. X-ray powder diffraction pattern of Form II of the
compound of formula (I). This pattern was obtained in accordance
with the procedures set forth in Example 18.
[0007] FIG. 3. X-ray powder diffraction pattern of the ethanolate
of the compound of formula (I). This pattern was obtained in
accordance with the procedures set forth in Example 18.
[0008] FIG. 4. X-ray powder diffraction pattern of Form IV of the
compound of formula (I) This pattern was obtained in accordance
with the procedures set forth in Example 18.
[0009] FIG. 5. X-ray powder diffraction pattern of Form V of the
compound of formula (I). This pattern was obtained in accordance
with the procedures set forth in Example 18.
[0010] FIG. 6. X-ray powder diffraction pattern of Form VI of the
compound of formula (I). This pattern was obtained in accordance
with the procedures set forth in Example 18.
DETAILED DESCRIPTION OF THE INVENTION
[0011] According to a first aspect of the invention there is
provided the compound of formula (I) in a novel crystalline form,
Form I. Form I is defined by the X-ray powder diffraction pattern
illustrated in FIG. 1, which is obtained by a properly aligned
diffractometer equipped with a diffracted beam curved graphite
monochromator using copper K.alpha. X-radiation. Form I may be
prepared from a mixture of the amorphous compound of formula (I)
and the novel crystalline Form II thereof by suspending and heating
in water or toluene at temperatures in excess of 50.degree. C. On
heating, the suspension turns to a sticky gum which on continued
heating converts to a solid.
[0012] In another aspect of the invention there is provided the
compound of formula (I) in a novel crystalline form, Form II. Form
II is defined by the X-ray powder diffraction pattern illustrated
in FIG. 2, which is obtained by a properly aligned diffractometer
equipped with a diffracted beam curved graphite monochromator using
copper K.alpha. X-radiation. Form II may be produced by
crystallization or recrystallization of the amorphous compound of
formula (I) from mixtures of methanol and water or methanol and
toluene. The initial product of the recrystallization is a methanol
solvate which on drying loses methanol to produce Form II.
[0013] In a further aspect of the invention there is provided the
compound of formula (I) as a solid white free flowing powder
(hereinafter referred to as the "ethanolate" or ethanol solvate of
the compound of formula (I)). The ethanolate is defined by the
X-ray powder diffraction pattern illustrated in FIG. 3, which is
obtained by a properly aligned diffractometer equipped with a
diffracted beam curved graphite monochromator using copper K.alpha.
X-radiation. The ethanolate may be prepared from solutions of the
compound in mixtures of ethanol and water or ethanol and toluene
mixtures.
[0014] In yet a further aspect of the invention, there is provided
the compound of formula (I) in a novel crystalline form, Form IV.
Form IV is defined by the X-ray powder diffraction pattern
illustrated in FIG. 4, which is obtained by a properly aligned
diffractometer equipped with a diffracted beam curved graphite
monochromator using copper K.alpha. X-radiation. Form IV may be
obtained by suspending and heating the amorphous compound of
formula (I) in water or toluene at temperatures in excess of
50.degree. C. Form IV may also be obtained by suspending Form II in
water for several months.
[0015] In a further aspect of the invention, there is provided the
compound of formula (I) in a novel crystalline form, Form V. Form V
is defined by the X-ray powder diffraction pattern illustrated in
FIG. 5, which is obtained by a properly aligned diffractometer
equipped with a diffracted beam curved graphite monochromator using
copper K.alpha. X-radiation. Form V may be produced by adding water
gradually to amorphous compound of formula (I) at around 70.degree.
C. with rapid stirring over 2 h. After heating at 65-70.degree. C.
with stirring for an additional 7 h, the heating and stirring may
be discontinued. The mixture may be allowed to stand at ambient
temperature for 2.5 days. The mixture may then be filtered. The
resultant grainy white solid residue may be allowed to air dry
overnight. Form V may also be prepared by hot water slurry of a
mixture of Form II and Form I at 90.degree. C. for 20 minutes. Form
V may also be prepared by solubilizing another crystalline form or
solvate of the compound of formula (I), preferrably Form VI or the
ethanolate, in acetonitrile and allowing the solution to stand at
ambient temperature until Form V precipitates out of solution.
[0016] In a further aspect of the invention, there is provided the
compound of formula (I) as a mixture of any two or more of the
anhydrous crystalline forms and/or solvates of the present
invention, or as a mixture of amorphous material and one or more of
the anhydrous crystalline forms and/or solvates of the present
invention. The compound of formula (I) may also be isolated by
acid/base precipitation.
[0017] As used herein, the term "solvate" is a complex of variable
stoichiometry formed by a solute (a compound of formula (I)) and a
solvent. Solvents, by way of example, include water, methanol,
ethanol, or acetic acid. Hereinafter, reference to a compound of
formula (I) is to the amorphous form of that compound, unless
another form or solvate thereof is specified.
[0018] The X-ray powder diffraction pattern of the various
anhydrous crystalline forms and solvates of the present invention
is determined using conventional techniques and equipment known to
those skilled in the art of physical characterization. The
diffraction patterns of FIGS. 1-6 were obtained with a Philips
X-Pert MPD diffractometer system equipped with a diffracted beam
curved graphite monochromator using copper K.alpha. X-radiation and
an automatic divergent slit. A xenon proportional counter was used
as the detector. The powder sample used to generate the X-ray
powder diffraction data was prepared by conventional back filled
sample preparation techniques using a 16 mm diameter holder about 2
mm thick.
[0019] A powder sample of each of Forms I, II, IV, V, VI and the
ethanolate were used to produce the X-ray powder diffraction
patterns of FIGS. 1, 2, 4, 5, 6 and 3, respectively. The X-ray
diffraction patterns for each of the various forms and solvates are
unique to the particular form. Each crystalline anhydrous form or
solvate exhibits a diffraction pattern with a unique set of
diffraction peaks which can be expressed in 2 theta angles
(.degree.), d-spacings (.ANG.) and/or relative peak
intensities.
[0020] 2 Theta diffraction angles and corresponding d-spacing
values account for positions of various peaks in the X-ray powder
diffraction pattern. D-spacing values are calculated with observed
2 theta angles and copper K.alpha.1 wavelength using the Bragg
equation. Slight variations in observed 2 theta angles and
d-spacings are expected based on the specific diffractometer
employed and the analyst's sample preparation technique. More
variation is expected for the relative peak intensities.
Identification of the exact crystal form of a compound should be
based primarily on observed 2 theta angles or d-spacings with
lesser importance placed on relative peak intensities. In a mixture
of crystal forms, the strongest diffraction peak for each form may
overlap with the diffraction peak of another form. In a mixture of
crystal forms, identification may be based on the presence of a
lesser intensity peak that does not overlap with the other crystal
forms. To identify 5,6-dichloro-2-(isopropylamino)-
-1-(.beta.-L-ribofuranosyl)-1H-benzimidazole Form I, the single
most characteristic 2 theta angle peak occurs at 2.57 degrees, or
34.35 .ANG. d-spacing. To identify
5,6-dichloro-2-(isopropylamino)-1-(.beta.-L-ribofu-
ranosyl)-1H-benzimidazole ethanolate, the single most
characteristic 2 theta angle peak occurs at 6.63 degrees, or 13.33
.ANG. d-spacing. To identify
5,6-dichloro-2-(isopropylamino)-1-(.beta.-L-ribofuranosyl)-1H-be-
nzimidazole Form IV, the single most characteristic 2 theta angle
peak occurs at 11.78 degrees, or 7.51 .ANG. d-spacing.
[0021] It may be desirable to rely upon multiple 2 theta angles or
multiple d-spacings for the identification of each of the various
anhydrous crystalline forms and/or solvates of the present
invention. Each of the various anhydrous crystalline forms and/or
solvates of
5,6-Dichloro-2-(isopropylamino)-1-(.beta.-L-ribofuranosyl)-1H-benzimidazo-
le can also be identified by the presence of multiple
characteristic 2 theta angle peaks including two, three, four,
five, six, seven, eight, nine, or ten of the 2 theta angles which
are reasonably characteristic of the particular crystalline form.
Typically, Form I can be identified by the presence of X-ray
diffraction peaks occurring at at least five of the following
positions, expressed in 2 theta angles: 7.90, 10.39, 14.63, 15.79,
20.75, 21.99, 22.77, 24.14, 24.71, and 25.97 degrees. Typically,
Form II can be identified by the presence of X-ray diffraction
peaks occurring at at least five of the following positions,
expressed in 2 theta angles: 7.91, 17.33, 18.23, 19.60, 21.88,
23.24, 23.92, 25.27, 27.70, and 29.21 degrees. The ethanolate can
be identified by the presence of X-ray diffraction peaks occurring
at at least five of the following positions, expressed in 2 theta
angles: 9.07, 10.38, 15.95, 17.72. 20.75, 21.37, 22.96, 23.93,
25.40, and 29.05 degrees. Form IV can be identified by the presence
of X-ray diffraction peaks occurring at at least five of the
following positions, expressed in 2 theta angles: 9.29, 16.04,
18.67. 22.06, 22.68, 23.34, 24.40, 29.64, 30.92, and 31.62 degrees.
Form V can be identified by the presence of X-ray diffraction peaks
occurring at at least five of the following positions, expressed in
2 theta angles: 13.30, 18.13, 18.78, 20.41, 21.75, 23.02, 26.87,
28.34, 28.55, and 30.22 degrees.
[0022] Some margin of error is present in each of the 2 theta angle
assignments and d-spacings reported above. The error in determining
d-spacings decreases with increasing diffraction scan angle or
decreasing d-spacing. The margin of error in the foregoing 2 theta
angles for Forms I, IV, V, and the ethanolate is approximately
.+-.0.05 degrees for each of the foregoing peak assignments. The
margin of error in the 2 theta angles for Form II is approximately
.+-.0.09 for each of the foregoing peak assignments. The margin of
error in d-spacing values for Forms I, IV, V, and the ethanolate is
approximately .+-.0.05 Angstroms. The margin of error in d-spacing
values for Form II is approximately .+-.0.09 Angstroms.
[0023] Since some margin of error is possible in the assignment of
2 theta angles and d-spacings, the preferred method of comparing
X-ray powder diffraction patterns in order to identify a particular
crystalline form is to overlay the X-ray powder diffraction pattern
of the unknown form over the X-ray powder diffraction pattern of a
known form. For example, one skilled in the art can overlay an
X-ray powder diffraction pattern of an unidentified crystalline
form of 5,6-dichloro-2-(isopropylamino)-1-(.b-
eta.-L-ribofuranosyl)-1H-benzimidazole, obtained using the methods
described herein, over FIG. 1 and readily determine whether the
X-ray diffraction pattern of the unidentified form is substantially
the same as the X-ray powder diffraction pattern of Form I. If the
X-ray powder diffraction pattern is substantially the same as FIG.
1, the previously unknown crystalline form can be readily and
accurately identified as Form I. The same technique can be used to
determine if the unidentified crystalline form is any of Forms II,
IV, V, or the ethanolate by overlaying the X-ray powder diffraction
pattern over FIGS. 2, 4, 5, or 3, respectively.
[0024] Although 2 theta angles or d-spacings are the primary method
of identifying a particular crystalline form, it may be desirable
to also compare relative peak intensities. As noted above, relative
peak intensities may vary depending upon the specific
diffractometer employed and the analyst's sample preparation
technique. The peak intensities are reported as intensities
relative to the peak intensity of the strongest peak. The intensity
units on the X-ray diffraction plot are counts/sec. The absolute
counts=counts/time.times.count time=counts/sec.times.10 sec.
Considering 2 theta angles, d-spacing (.ANG.) and relative peak
intensity (I) of the fifteen most intense peaks, obtained by the
method of Example 18 below, Form I
5,6-dichloro-2-(isopropylamino)-1-(.beta.-L-ribofuranosy-
l)-1H-benzimidazole exhibits the following X-ray diffraction
pattern characteristics:
1 Form I 2 theta angle (.degree.).sup.1 .ANG..sup.1 I 7.90 11.19
58.8 10.39 8.51 49.7 14.63 6.05 33.3 15.79 5.61 46.1 16.95 5.23
16.4 19.24 4.61 14.4 20.75 4.28 29.4 21.99 4.04 21.0 22.77 3.90
100.0 24.14 3.68 35.2 24.71 3.60 20.5 25.72 3.46 13.9 25.97 3.43
43.2 29.44 3.03 13.9 31.09 2.87 14.7 .sup.1Margin of error =
approx. .+-. 0.05
[0025] Form II
5,6-dichloro-2-(isopropylamino)-1-(.beta.-L-ribofuranosyl)--
1H-benzimidazole is further characterized by the following 2 theta
angles, d-spacings, and relative peak intensities of the fifteen
most intense peaks, obtained by the method of Example 18 below.
2 Form II 2 theta angle (.degree.).sup.1 .ANG..sup.1 I 7.91 11.17
100.0 10.86 8.14 10.1 12.69 6.97 5.2 13.65 6.48 4.7 14.94 5.93 8.4
16.11 5.50 12.8 17.33 5.11 17.5 18.23 4.86 18.2 19.60 4.53 19.6
21.88 4.06 18.8 23.24 3.82 19.0 23.92 3.72 26.7 25.27 3.52 24.5
27.70 3.22 34.9 29.21 3.06 14.2 .sup.1Margin of error = approx.
.+-. 0.09
[0026] Form II may also exhibit peaks at essentially the following
2 theta angles: 7.9, 10.9, 16.1, 17.3, 18.2, 19.6, 21.9, 23.9
degrees.
[0027] The ethanolate of
5,6-dichloro-2-(isopropylamino)-1-(.beta.-L-ribof-
uranosyl)-1H-benzimidazole is further characterized by the
following 2 theta angles, d-spacings, and relative peak intensities
of the fifteen most intense peaks, obtained by the method of
Example 18 below.
3 Ethanolate 2 theta angle (.degree.).sup.1 .ANG..sup.1 I 9.07 9.74
45.2 10.38 8.52 22.7 15.95 5.55 40.4 17.72 5.00 100.0 18.96 4.68
17.2 19.79 4.48 18.4 20.75 4.28 30.4 21.37 4.16 27.7 21.89 4.06
19.0 22.08 4.02 17.5 22.96 3.87 40.6 23.93 3.72 41.3 25.40 3.50
26.7 27.65 3.22 19.8 29.05 3.07 25.4 .sup.1Margin of error =
approx. .+-. 0.05
[0028] The ethanolate may also exhibit peaks at essentially the
following 2 theta angles: 6.6, 9.1, 9.4, 10.4, 11.0, 14.7, 16.0,
17.2, 17.7, 18.3, 20.8, 21.4, 23.0, 23.9, 25.4, 27.7, 29.1
degrees.
[0029] Form IV
5,6-dichloro-2-(isopropylamino)-1-(.beta.-L-ribofuranosyl)--
1H-benzimidazole is further characterized by the following 2 theta
angles, d-spacings, and relative peak intensities of the fifteen
most intense peaks, obtained by the method of Example 18 below.
4 Form IV 2 theta angle (.degree.).sup.1 .ANG..sup.1 I 9.29 9.51
15.6 11.78 7.51 12.5 16.04 5.52 20.1 18.67 4.75 25.1 19.54 4.54
11.5 22.06 4.03 100.0 22.39 3.97 11.6 22.68 3.92 17.9 23.34 3.81
15.5 23.68 3.75 10.0 24.40 3.65 28.7 28.72 3.11 11.1 29.64 3.01
13.0 30.92 2.89 26.5 31.62 2.83 13.9 .sup.1Margin of error =
approx. .+-. 0.05
[0030] Form IV may also exhibit peaks at essentially the following
2 theta angles: 7.5, 9.3, 11.8, 16.0, 18.7, 19.4, 19.5, 22.1, 22.7,
24.4, 29.6, 30.9 degrees.
[0031] Form V
5,6-dichloro-2-(isopropylamino)-1-(.beta.-L-ribofuranosyl)-1-
H-benzimidazole is further characterized by the following 2 theta
angles, d-spacings, and relative peak intensities of the fifteen
most intense peaks, obtained by the method of Example 18 below.
5 Form V 2 theta angle (.degree.).sup.1 .ANG..sup.1 I 9.07 9.75
19.1 9.35 9.46 14.3 10.74 8.23 14.0 13.30 6.65 26.1 17.04 5.20 18.5
18.13 4.89 39.2 18.78 4.72 57.0 20.41 4.35 39.5 21.75 4.08 100.0
22.71 3.91 15.8 23.02 3.86 20.3 26.87 3.32 23.4 28.34 3.15 24.7
28.55 3.12 51.1 30.22 2.95 39.0 .sup.1Margin of error = approx.
.+-. 0.05
[0032] Form V may also exhibit peaks at essentially the following 2
theta angles: 9.1, 9.3, 10.7, 13.3. 17.0, 18.1, 18.8, 20.4, 21.8,
26.9, 28.6, 30.2 degrees.
[0033] Based upon the foregoing characteristic features of the
X-ray powder diffraction patterns of Forms I, II, IV, V, and the
ethanolate and the methods described herein for obtaining these
X-ray powder diffraction patterns, one skilled in the art can
readily identify each of these anhydrous crystalline forms or
solvates of 5,6-dichloro-2-(isopropylamino-
)-1-(.beta.-L-ribofuranosyl)-l1H-benzimidazole. It will be
appreciated by those skilled in the art that the X-ray powder
diffraction pattern of a sample of any particular anhydrous
crystalline form or solvate, obtained using the methods described
herein, may exhibit additional peaks. The foregoing tables provide
the fifteen most intense peaks which are characteristic of that
particular crystalline form or solvate.
[0034] The tables should not be interpreted as an exhaustive list
of peaks exhibited by the particular form or solvate.
[0035] Other methods of physical characterization can also be
employed to identify the anhydrous crystalline forms or solvates of
the present invention. For example, melting point, differential
scanning calorimetry, infra red spectra, and moisture sorption are
all techniques known to those skilled in the art to be useful for
the physical characterization of a crystalline form or solvate.
These techniques may be employed alone or in combination to
characterize a given anhydrous crystalline form or solvate.
[0036] The invention relates to the anhydrous crystalline forms and
solvates both in pure form and in admixture with other forms or
solvates of the compound of formula (I). For example, Form I may be
in admixture with any one or more of Forms II, IV, V, or the
ethanolate. Alternatively Form I may be in admixture with amorphous
compound of formula (I). In another embodiment, Form I is in
admixture with both amorphous compound of formula (I) and one or
more other crystalline forms or solvates including Forms II, IV, V
and the ethanolate. Similarly, any of Forms II, IV, V, or the
ethanolate may form admixtures with another form or solvate and/or
the amorphous material. One embodiment of the present invention is
an admixture of Forms I and V. Another embodiment of the present
invention is an admixture of Form II and the amorphous material.
Another embodiment of the present invention is an admixture of
Forms I, IV, and V. Still another embodiment of the present
invention is an admixture of Forms I, IV, V, and the amorphous
material. Other admixtures of two or more of the anhydrous
crystalline forms or solvates which are contemplated by the present
invention can be readily determined by those skilled in the
art.
[0037] The present invention expressly contemplates the foregoing
mixtures of any anhydrous crystalline form or solvate with one or
more of the amorphous compound of formula (I), and/or other
anhydrous crystalline forms and solvates It should be understood
that admixtures of a particular form or solvate with amorphous
compound of formula (I) and/or other crystalline forms or solvates
may result in the masking or absence of one or more of the
foregoing X-ray powder diffraction peaks described above for that
particular form. Methods are known in the art for analyzing such
admixtures of crystalline forms in order to provide for the
accurate identification of the presence or absence of particular
crystalline forms in the admixture.
[0038] In addition to the foregoing, any of the anhydrous
crystalline forms or solvates of the present invention may be in
admixture with hydrated crystalline forms. For example in any batch
containing the anhydrous crystalline compound of formula (I), there
may also be hydrated crystalline forms of the compound.
[0039] According to a further aspect, the present invention
provides a process for the production of the compound of formula
(I) in anhydrous crystalline form which comprises treating the
amorphous compound of formula (I) with a solubilising solvent
serving to convert an amount of the compound of formula (I) into
one or more of the anhydrous crystalline forms and/or solvates.
[0040] The invention also provides a process for the production of
the compound of formula (I) in an anhydrous crystalline form, said
process comprising the steps of:
[0041] a) forming or providing compound of formula (I) in solution
in free base or salt form;
[0042] b) isolating the compound of formula (I) from the solution
and optionally removing unbound (damp, non-solvated) solvent
leaving the compound of formula (I) in substantially dry form;
[0043] c) treating the compound of formula (I) with a solubilizing
solvent serving to convert an amount of the optionally dried
compound of formula (I) from step b) into the anhydrous crystalline
form; and
[0044] d) isolating the anhydrous crystalline form.
[0045] The compound of formula (I) may be prepared by any method
known in the art, but preferably by the methods described in WO
96/01833, incorporated herein by reference in its entirety.
[0046] The synthesis of the compound of formula (I) generally leads
to the formation of the compound in solution in the reaction
mixture from which it may be separated and purified as a solid
product. The compound of formula (I) may then optionally be dried.
A number of factors influence the crystalline form of the solid
product and in accordance with the present invention the conditions
of separation and/or subsequent processing are adjusted to produce
the compound of formula (I) as one particular anhydrous crystalline
form or solvate, or as a mixture of two or more anhydrous
crystalline forms or solvates.
[0047] A suitable solubilizing solvent is preferably a
water-soluble organic solvent and should be sufficiently
solubilizing and be employed in an amount to allow partial
solubilization to effect the conversion and precipitation for
example from hydrated crystalline form to the desired anhydrous
crystalline form of the compound of formula (I). Advantageously the
solvent is eventually removed by drying under vacuum.
[0048] The damp compound of formula (I) following the first
isolation (as in step b above) is preferably dried, for example at
about 30.degree. to about 70.degree. C. to provide substantially
dry compound of formula (I).
[0049] The present invention also provides crystalline forms and
solvates of the compound of formula (I) for use in medical therapy,
e.g. in the treatment or prophylaxis, including suppression of
recurrence of symptoms, of a viral disease in an animal, e.g. a
mammal such as a human. The compound of formula (I) anhydrous
crystalline forms and solvates are especially useful for the
treatment or prophylaxis of viral diseases such as herpes virus
infections, for example, CMV infections, as well as disease caused
by hepatitis B and hepatitis C viruses. In addition to its use in
human medical therapy, the compound of formula (I) anhydrous
crystalline forms and solvates can be administered to other animals
for treatment or prophylaxis of viral diseases, e.g. to other
mammals.
[0050] The present invention also provides a method for the
treatment or prophylaxis of a viral infection, particularly a
herpes infection, CMV infections, as well as disease caused by
hepatitis B and hepatitis C viruses in an animal, e.g. a mammal
such as a human, which comprises administering to the animal an
effective antiviral amount of the compound of formula (I) as an
anhydrous crystalline form or solvate.
[0051] The present invention also provides the use of the compound
of formula (I) anhydrous crystalline forms and solvates in the
preparation of a medicament for the treatment or prophylaxis of a
viral infection.
[0052] As used herein, the term prophylaxis includes the prevention
of infection, the prevention of occurrence of symptoms and the
prevention of recurrence of symptoms.
[0053] The compound of formula (I) anhydrous crystalline forms and
solvates may be administered by any route appropriate to the
condition to be treated, but the preferred route of administration
is oral. It will be appreciated however, that the preferred route
may vary with for example the condition of the recipient.
[0054] For each of the above-indicated utilities and indications
the amounts required of the active ingredient (as above defined)
will depend upon a number of factors including the severity of the
condition to be treated and the identity of the recipient and will
ultimately be at the discretion of the attendant physician or
veterinarian. In general however, for each of these utilities and
indications, a suitable effective dose will be in the range of 0.01
to 250 mg per kilogram body weight of recipient per day,
advantageously in the range of 0.1 to 100 mg per kilogram body
weight per day, preferably in the range of 0.5 to 30 mg per
kilogram body weight per day, particularly 1.0 to 30 mg per
kilogram body weight per day (unless otherwise indicated, all
weights of the active ingredient are calculated with respect to the
free base of the compound of formula (I)). The desired dose is
preferably presented as one, two, three or four or more subdoses
administered at appropriate intervals throughout the day. These
sub-doses may be administered in unit dosage forms, for example,
containing about 10 to 1200 mg, or 50 to 500 mg, preferably about
20 to 500 mg, and most preferably 100 to 400 mg of active
ingredient per unit dose form.
[0055] While it is possible for the active ingredient to be
administered alone, it is preferable to present it as a
pharmaceutical formulation. The formulation comprises the active
ingredient as above defined, together with one or more
pharmaceutically acceptable excipients therefor and optionally
other therapeutic ingredients. The excipient(s) must be
"acceptable" in the sense of being compatible with the other
ingredients of the formulation and not deleterious to the recipient
thereof.
[0056] The formulations include those suitable for oral
administration and may conveniently be presented in unit dosage
form prepared by any of the methods well known in the art of
pharmacy. Such methods include the step of bringing into
association the active ingredient with the carrier which
constitutes one or more accessory ingredients. In general, the
formulations are prepared by uniformly and intimately bringing in
to association the active ingredient with liquid carriers or finely
divided solid carriers or both, and then, if necessary, shaping the
product.
[0057] Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules,
cachets, sachets of granules or tablets (such as a swallowable,
dispersible or chewable tablet) each containing a predetermined
amount of the active ingredient; as a powder or granules; as a
solution or a suspension in an aqueous liquid or a non-aqueous
liquid; or as an oil-in-water liquid emulsion or a water-in-oil
liquid emulsion. The active ingredient may also be presented as a
bolus, electuary or paste.
[0058] A tablet may be made by compression or moulding optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with a binder, lubricant, inert diluent, preservative,
surface active or dispersing agent. Moulded tablets may be made by
moulding in a suitable machine a mixture of the powdered compound
moistened with an inert liquid diluent. The tablets may optionally
be coated or scored any may be formulated so as to provide slow or
controlled release of the active ingredient therein.
[0059] In addition to the oral dosage forms described hereinabove,
the anhydrous crystalline forms and solvates of the present
invention may also be formulated for administration by topical,
parenteral, and other administration routes using the carriers and
techniques described in WO96/01833. It will be appreciated by those
skilled in the art that the preparation of dosage forms as
solutions of the anhydrous crystalline forms or solvates
substantially completely dissolved in a solvent, e.g. for
parenteral administration, will preclude the identification of the
particular crystalline form utilized in the preparation of the
solution. Nevertheless, each of the anhydrous crystalline forms and
solvates can be used for the preparation of solutions by
substantially completely solubilizing the crystalline form or
solvate in a suitable solvent
[0060] Preferred unit dosage formulations are those containing a
daily dose or unit daily sub-dose (as herein above recited) or an
appropriate fraction thereof, of the active ingredient.
[0061] It should be understood that in addition to the ingredients
particularly mentioned above the formulation of this invention may
include other agents conventional in the art having regard to the
type of formulation in question, for example those suitable for
oral administration may include flavoring agents or taste masking
agents.
[0062] The following examples are intended for illustration only
and are not intended to limit the scope of the invention in any
way.
EXAMPLE 1
5,6,-Dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-benzimidazole
Form I
[0063] The compound of formula (I) (200 mg) was placed in a Thermal
Activity Monitor (TAM) and a few drops of water were added to make
the powder wet. The vial was sealed and placed in a TAM chamber at
50.degree. C. The mixture was cooled to ambient temperature and
filtered. The damp residue was dried in vacuo at 60.degree. C.
overnight to give the compound of formula (I) Form I.
[0064] The X-ray powder diffraction pattern of the product of
Example 1 is shown in FIG. 1.
EXAMPLE 2
5,6,-Dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-benzimidazole
Form I
[0065] The compound of formula (I) (1.5 g) was suspended in water
(30 ml) and heated to 65.degree. C. with stirring. After
approximately 0.5 h, stirring became difficult as a gum formed.
After further heating, the gum turned solid and was broken up with
a spatula. The mixture was heated at 65-70.degree. C. for 9 h. The
mixture was cooled to 20.degree. C. and the solid collected by
filtration and dried in vacuo at 40.degree. C. for 24 h to give the
compound of formula (I) Form I.
[0066] The X-ray powder diffraction pattern of the product of
Example 2 is shown in FIG. 1.
EXAMPLE 3
5,6,-Dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-benzimidazole
Form I
[0067] The compound of formula (I) (5 g) and water (1.5 ml) were
stirred and heated in an oil bath at 80.degree. C. The powder
turned to a gum and stirring ceased. Heating was continued for 8 h.
The solid was loosened with a spatula and stirred occasionally.
After cooling to 20.degree. C., the solid was collected and dried
in vacuo at 40.degree. C. for 4 h.
[0068] The X-ray powder diffraction pattern of the product of
Example 3 is shown in FIG. 1.
EXAMPLE 4
5,6,-Dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-benzimidazole
Form I
[0069] The compound of formula (I) (2 g) in toluene (15 ml) was
heated at reflux for 19 h. On heating the suspension turned to a
gum that solidified on further heating. The solid was collected by
filtration and dried in vacuo at 40.degree. C. to yield the
compound of formula (I).
[0070] The X-ray powder diffraction pattern of the product of
Example 4 is shown in FIG. 1.
EXAMPLE 5
Preparation of
5,6,-dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1-
H-benzimidazole Form I from Form II
[0071] The compound of formula (I) Form II (2 g) in toluene (10 ml,
5 vol) was heated to 60.degree. C., at which point the solid began
to stick to the sides of the flask. On continued heating to
95.degree. C., an oil formed. Heating was continued to 105.degree.
C., then toluene (2.5 vol) was added and heating continued. Reflux
was continued for 3 h with rapid stirring. The oil bath temperature
was reduced to 80.degree. C. (internal temperature 73.degree. C.)
and heating continued for 3 h again with rapid stirring. The
mixture was heated to reflux again for 16 h and then allowed to
cool to room temperature. The loose solid was collected by
filtration washing with toluene (2.times.5 ml) and dried in vacuo
at 20.degree. C. and at 40.degree. C. in vacuo to yield a white
solid. The residual solid was removed from the flask, collected by
filtration, and dried in vacuo at 20.degree. C. The filtrate was
concentrated under reduced pressure to yield a solid.
[0072] The X-ray powder diffraction pattern of the product of
Example 5 is shown in FIG. 1.
EXAMPLE 6
Preparation of
5,6,-dichloro-2-(isopropylamino)-1-p-L-ribofuranosyl-1H-ben-
zimidazole Form I from Form II
[0073] The compound of formula (I) (5 g) was stirred with water
(1.5 ml) in an oil bath at 80.degree. C. When the temperature of
the oil bath reached about 60.degree. C., the mixture became
difficult to stir. Heating continued for 8 h with occasional
stirring and then cooled to room temperature. The material was
dried in vacuo at 40.degree. C. for 4 h
[0074] The X-ray powder diffraction pattern of the product of
Example 6 is shown in FIG. 1.
EXAMPLE 7
5,6,-Dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-benzimidazole
Form II
[0075] The compound of formula (I) (100 g) was added to stirred
toluene/methanol (4:1, 440 ml) and heated to 65.degree. C. to give
a clear solution. The solution was clarified through a filter with
a line wash (toluene/methanol [4:1, 110 ml, warm]). The solution
was heated back to 65.degree. C. and toluene (4.5 vol) was added
slowly, maintaining internal temperature above 65.degree. C. When
the addition was complete, the solution was cooled to 40.degree. C.
over 1 h and aged at 40.degree. C. After 0.5 h, the mixture was
seeded with the compound of formula (I) Form II and then aged for a
further 4.5 h. The suspension was cooled to 20.degree. C. over 1 h
and aged at 20.degree. C. for 12 h and then cooled to 5.degree. C.
over 1 h and aged for 3 h. The solid was collected by filtration,
washing with toluene (2.times.100 ml). The wet cake was transferred
to a dryer and dried in vacuo at 20.degree. C.
[0076] The X-ray powder diffraction pattern of the product of
Example 7 is shown in FIG. 2.
EXAMPLE 8
5,6,-Dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-benzimidazole
Form II
[0077] The compound of formula (I) (1.0 wt) was dissolved in ethyl
acetate (6.0 vol) and subjected to a finishing filtration. The
filtrates were concentrated to approximately 3 volumes. Assuming
complete solvent exchange, the solution was reconstituted to 3.5
volumes with methanol. Water (0.5 vol) was added and the solution
was cooled to 0-5.degree. C. The crystallization was seeded with a
small amount of pure the compound of formula (I) and the solution
was stored at 0-5.degree. C. for 2 h. The product was filtered (no
wash) and dried in vacuo for 24-48 h at ambient temperature. A
second crop was obtained by evaporation of the filtrate to half
volume followed by cooling, seeding, and crystallization in a
similar manner as above.
[0078] The X-ray powder diffraction pattern of the product of
Example 8 is shown in FIG. 2.
EXAMPLE 9
5,6,-Dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-benzimidazole
Form II
[0079] The compound of formula (I) (10 g) was dissolved in methanol
(20 ml) with heating to 50.degree. C. Water (5 ml) was added and
the mixture cooled to 5.degree. C. slowly and was stirred at
5.degree. C. for 1 h. The solid was collected by filtration and
dried in vacuo at 20.degree. C. for 15 h and at 40.degree. C. for 4
h to yield the compound of formula (I).
[0080] The X-ray powder diffraction pattern of the product of
Example 9 is shown in FIG. 2.
EXAMPLE 10
Preparation of mixtures of
5,6,-dichloro-2-(isopropylamino)-1-.beta.-L-rib-
ofuranosyl-1H-benzimidazole forms
[0081] The compound of formula (I) may be dissolved in 2N
hydrochloric acid (60 ml) and stirred for 0.5 h and filtered. The
filtrate was heated to 60.degree. C. and 2N sodium hydroxide (55
ml) was added slowly, maintaining the internal temperature between
60-70.degree. C. during the addition. The mixture was stirred at
65-70.degree. C. for 2 h and then cooled to 20.degree. C. over 2 h.
The solid was collected by filtration, washing with water
(2.times.30 ml) and dried in vacuo at 40.degree. C. for 16 h to
yield the compound of formula (I) (8.8 g, 88%).
EXAMPLE 11
5,6,-Dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-benzimidazole
ethanolate
[0082] The compound of formula (I) (1.0 wt) was suspended in
ethanol/water (10.0 vol) at 70.degree. C. for 2 h. The
ethanol/water (v/v) ratios were as follows: 10/90, 15/85, 20/80,
25/75 and 30/70. The resulting solid white free flowing powder was
filtered and air-dried. Ethanol solvate was obtained in similar
manner from solutions of ethanol/toluene (ratios 5/95, 10/90,
15/85, 20/80, 25/75, and 30/70).
[0083] The X-ray powder diffraction pattern of the product of
Example 11 is shown in FIG. 3.
EXAMPLE 12
5,6,-Dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-benzimidazole
ethanolate
[0084] The compound of formula (I) (20 g) was added to stirred
toluene/ethanol (7:1, 200 ml) and heated to reflux (81.degree. C.)
to give a clear solution. The solution was cooled to 20.degree. C.
and crystallization occurred at approximately 50.degree. C. The
suspension was cooled to 0-5.degree. C. and aged for 2 h. The solid
was collected by filtration, and washed with toluene (2.times.20
ml). The wet cake was dried in vacuo at 40.degree. C.
[0085] Recrysallization of the compound of formula (I) from
ethanol/water or ethanol/toluene gave an ethanol solvate containing
0.5 moles of ethanol per mole of the compound of formula (I).
[0086] The X-ray powder diffraction pattern of the product of
Example 12 is shown in FIG. 3.
EXAMPLE 13
5,6,-Dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-benzimidazole
Form IV
[0087] Water (300 ml) was added to Form I (4 g) as prepared in
Example 1 above and stirred for 20 min. The mixture was then heated
at 50.degree. C. for 6 days, and then cooled to room temperature.
The solid, grainy crystalline material was filtered and dried in
vacuo at 60.degree. C.
[0088] The X-ray powder diffraction pattern of the product of
Example 13 is shown in FIG. 4.
EXAMPLE 14
5,6,-Dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-benzimidazole
Form V
[0089] The compound of formula (I) (2.0 g) was added gradually to
water (40 ml) at 70.degree. C. with rapid stirring over 2 h. after
heating at 65-70.degree. C. with stirring for an additional 7 h,
the heating and stirring were discontinued. After sitting for 2.5
days at ambient temperature, the mixture was filtered the grainy
white solid residue was allowed to air dry overnight affording the
compound of formula (I) Form V.
[0090] The X-ray powder diffraction pattern of the product of
Example 14 is shown in FIG. 5.
EXAMPLE 15
5,6,-Dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-benzimidazole
Form V
[0091] The compound of formula (I) Form VI (72.86 mg), was added to
1 ml of acetonitrile and completely dissolved. Upon standing for
about 30 days at ambient temperature, large crystals precipitated
out of the solution, affording the compound of formula (I) Form
V.
[0092] The X-ray powder diffraction pattern of the product of
Example 15 is shown in FIG. 5.
EXAMPLE 16
5,6,-Dichloro-2-(isopropylamino)-1-.beta.-L-ribofuranosyl-1H-benzimidazole
Form VI
[0093] The compound of formula (I) ethanolate (200 mg) was weighed
into small vials. Hydrostats with NaCl saturated solutions and
excess NaCl solid were inserted inside the vials. The vials were
then sealed very well and stored at 80.degree. C. The samples were
removed from the vial and heated to 170.degree. C. on a
differential scanning calorimeter and subsequently cooled to room
temperature. The powder was collected from DSC pans and analyzed by
X-ray diffraction.
[0094] Characterization: The X-ray powder diffraction pattern of
the product of Example 16 (Form VI) is shown in FIG. 6. The
following data, measured in 2 theta angles, d-spacings, relative
intensities, and Miller indices were obtained:
6TABLE 1 X-ray Powder Diffraction of Form VI of 1263W94 2 .theta.
(.degree.) .sup.1 .ANG. .sup.2 I h .sup.3 k .sup.3 l .sup.3 8.53
10.36 14.5 0 0 4 10.47 8.45 25.6 1 0 2 12.80 6.91 16.8 0 0 6 14.16
6.25 16.4 1 1 2 13.51 6.55 21.4 1 1 0 14.95 5.92 60.4 1 1 3 15.98
5.54 26.2 1 1 4 17.23 5.14 100.0 1 1 5 19.25 4.61 19.3 2 0 1 21.41
4.15 26.5 2 1 0 21.83 4.07 60.4 2 1 2 22.35 3.97 38.3 2 1 3 23.07
3.85 48.7 2 1 4 27.49 3.24 30.9 2 1 8 30.11 2.97 18.5 2 2 6 .sup.1
Margin of error is approx. .+-.0.05 degrees. .sup.2 Margin of error
is approx. .+-.0.05 .ANG.. .sup.3 The Miller indices, h, k, and I
above are used to define uniquely a set of parallel planes in the
crystal.
EXAMPLE 17
Preparation of
5,6-dichloro-2-(isopropylamino)-1-(beta-L-ribofuranosyl)-1H-
-benzimidazole Form VI by Crystallization from Ethyl
Acetate/Toluene
[0095] Sodium hydroxide (2M, 1790 ml) was added to a slurry of
5,6-dichloro-2-(isopropylamino)-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosy-
l)-1H-benzimidazole(358 g) in TMBE (1790 ml) containing methanol
(179 ml). The mixture was stirred at 25-30.degree. C. until the
reaction was complete. The layers were separated and the aqueous
layer further extracted with TBME (716 ml) The combined organic
solutions were washed with 10% brine (2.times.1790 ml). The organic
solution was concentrated at atmospheric pressure to about 2.5 vol
(895 ml). Ethyl acetate (2864 ml) was added and the solution was
again concentrated to about 2.5 vol. The solution was cooled to
40-50.degree. C., and the resulting solution was clarified, rinsing
with an ethyl acetate (716 ml) line wash. The clarified solution
was concentrated at atmospheric pressure to about 3.3 vol (1180
ml).
[0096] The solution was heated to 60.degree. C. Toluene (3000 ml)
was heated to 60.degree. C. and added over 1 h to the ethyl acetate
solution. The resulting mixture was aged at 60.degree. C. overnight
before cooling to 0-5.degree. C. over 1 h then aging at 0.5.degree.
C. for about 2 h. The slurry was filtered, washed with ethyl
acetate:toluene 1:4 (2.times.716 ml) and dried in vacuo at
40.degree. C. for 18 h to yield
5,6-dichloro-2-(isopropylamino)-1-(beta-L-ribofuranosyl)-1H-benzimidazole
Form VI
[0097] Characterization: as for Example 16.
EXAMPLE 18
Experimental Methods for Characterization of Crystalline Forms and
Solvates
[0098] X-Ray Powder Diffraction
[0099] The X-ray powder diffraction patterns were determined on a
Philips X'Pert MPD diffractometer equipped with diffracted beam
curved graphite monochromator using copper K.alpha. X-radiation and
an automatic divergent slit. The diffractometer was run in the step
scan mode at 0.04.degree. per step and a 1 second count per step. A
xenon proportional counter with a graphite monochromator was used
as the detector. Samples were back filled into a 16 mm diameter
holder having a thickness of about 2 mm. The X-ray Powder
Diffraction Patterns of Forms I, II, IV, V, VI and the ethanolate
are provided in FIGS. 1, 2, 4, 5, 6 and 3, respectively.
EXAMPLE 19
Tablet Formulation
[0100] Formulation A
7 1263W94 Ethanolate Tablets Direct Compression Potency 100 mg 400
mg Core Ingredients 1263W94 Ethanolate 105.9.sup.2 423.6.sup.3
Microcrystalline Cellulose, NF 200.0 800.0 Crospovidone, NF 20.0
80.0 Magnesium Stearate, NF 0.8 3.2 Total (core) 0326.7 mg 1306.8
mg Coating Ingredients Opadry White YS-1-18034 9.0 36.0 Purified
Water USP.sup.1 QS QS Total (core) 335.7 mg 1342.8 mg Theoretical
Batch Size (cores) kg 0.8168 tablets 2500 .sup.1Removed during
processing .sup.2Equivalent to 100 mg of 1263W94 per tablet
.sup.3Equivalent to 400 mg of 1263W94 per tablet
[0101]
8 1263W94 Tablets (form II/amorphous) Direct Compression Potency
100 mg 400 mg Core Ingredients 1263W94 103.3.sup.2 413.2.sup.3
Lactose, anhydrous, NF 65.0 260.0 Microcrystalline Cellulose, NF
20.0 80.0 Crospovidone, NF 12.0 48.0 Magnesium Stearate, NF 1.0 4.0
Total (core) 201.3 mg 805.2 mg Coating ingredients Opadry White
YS-1-18034 6.0 24.0 Purified Water USP.sup.1 QS QS Total (core)
207.3 mg 829.2 mg Theoretical Batch Size (cores) kg 0.785 tablets
3900 .sup.1Removed during processing .sup.2Equivalent to 100 mg of
1263W94 per tablet .sup.3Equivalent to 400 mg of 1263W94 per
tablet
Manufacturing Procedure for Direct Compression
[0102] All ingredients were screened, except the magnesium
stearate, using 20 or 30 mesh. All ingredients were blended,
excluding the magnesium stearate, until uniform. The magnesium
stearate was screened as above. The magnesium stearate was added to
the other ingredients and blended. The tablets were compressed
using a rotary press. A 10% coating suspension was prepared by
mixing Opadry with water. Tablets were coated to a weight gain of
approximately 3%.
[0103] Formulation B
9 1263W94 Ethanolate Tablets Wet Granulation Potency 100 mg 400 mg
Core Ingredients 1263W94 Ethanolate 105.9.sup.2 423.6.sup.3
Microcrystalline Cellulose, NF 75.0 300.0 Crospovidone, NF 15.0
60.0 Povidone, USP, K30 7.5 30.0 Magnesium Stearate, NF 0.6 2.4
Purified Water USP.sup.1 QS QS Total (core) 204.0 mg 816.0 mg
Coating Ingredients Opadry White YS-1-18034 6.0 24.0 Purified Water
USP.sup.1 QS QS Total (core) 210.0 mg 840.0 mg Theoretical Batch
Size (cores) kg 0.714 tablets 3500 .sup.1Removed during processing
.sup.2Equivalent to 100 mg of 1263W94 per tablet .sup.3Equivalent
to 400 mg of 1263W94 per tablet
[0104]
10 1263W94 Tablets (form II/amorphous) Wet Granulation Potency 100
mg 400 mg Core Ingredients 1263W94 103.3.sup.2 413.2.sup.3 Lactose,
anhydrous, NF 60.0 240.0 Microcrystalline Cellulose, NF 200 80.0
Crospovidone, NF 12.0 48.0 Povidone, USP, K30 6.0 24.0 Sodium
Lauryl Sulfate, NF 2.0 8.0 Colloidal Silicon Dioxide, NF 0.6 2.4
Magnesium Stearate, NF 1.0 4.0 Purified Water USP.sup.1 QS QS Total
(core) 204.9 mg 819.6 mg Coating Ingredients Opadry White
YS-1-18034 6.0 24.0 Purified Water USP.sup.1 QS QS Total (core)
210.9 mg 843.6 mg Theoretical Batch Size (cores) kg 0.799 tablets
3900 .sup.1Removed during processing .sup.2Equivalent to 100 mg of
1263W94 per tablet .sup.3Equivalent to 400 mg of 1263W94 per
tablet
Manufacturing Procedure for Wet Granulation
[0105] The granule ingredients were screened using a 20 or 30 mesh.
The granule ingredients were dry blended in a high shear granulator
until uniform and then granulated in a high shear granulator using
purified water. The granule was dried to a loss on drying of less
than 2%. The granule was screened as above. The remaining
ingredients were screened as above. The granule was blended with
the remaining ingredients. The tablets were compressed using a
rotary press. A 10% coating suspension was prepared by mixing
Opadry with water. Tablets were coated to a weight gain of
approximately 3%.
EXAMPLE 20
Capsule Formulation
[0106] The following formulation may be prepared as follows using
the compound of formula (I) Form II.
11 1263W94 Capsules (form II) Potency 100 mg Capsule Fill
Ingredients 1263W94 (active) 101.0.sup.1 Lactose, Anhydrous NF
232.0 Crospovidone, NF 17.0 Magnesium Stearate, NF 1.0 Total Fill
Weight 351.0 mg Capsule Shell Gelatin, while opaque cap and 81.1
body Total Weight 432.5 mg .sup.1Equivalent to 100 mg of 1263W94
per tablet
Manufacturing Procedure for Capsules
[0107] The capsule fill ingredients are mixed using a mortar and
pestle by geometric dilution. The combined capsule fill ingredients
are filled into the gelatin capsules by hand. Capsules are closed
by hand.
EXAMPLE 21
Oral Suspension Formulation
[0108] The following formulation may be prepared as follows using
the compound of formula (I) Form I, II, V or an admixture of Forms
I and V.
12 1263W94 Oral Suspension Potency 30 mg/ml Ingredients per 100 ml
1263W94 (active) 3.0 g Sucrose 50.0 g Propylene Glycol 5.0 g Sodium
Chloride 0.5 g Citric Acid QS Sodium Citrate QS Microcrystalline
Cellulose 2.5 g and Sodium Carboxy- methylcellulose Sodium
Carboxymethyl- 0.25 g cellulose Polysorbate 80 0.2 g Sodium
Benzoate 0.1 g Methylparaben 0.1 g Flavorant 0.2 ml Colorant 0.005
g Purified Water USP QS Total Volume 100.0 ml
Manufacturing Procedure for Oral Solution
[0109] Sucrose is dissolved in purified water to approximately 70%
of total batch volume. While mixing continuously, sodium chloride,
citric acid, sodium citrate, and sodium benzoate are added and
dissovled. If necessary, the pH is adjusted to between 5.0 and 6.0,
by adding sufficient citric acid or sodium citrate as necessary.
Microcrystalline cellulose and sodium carboxymethylcellulose
(Avicel RC 591) are added while mixing and mixing is continued
until a uniform, smooth dispersion is formed. Polysorbate 80 is
added while mixing. In a separate vessel, methylparaben is
dissolved in propylene glycol and sodium carboxy methyl cellulose
(0.25 g) is dispersed, and this liquid is added to the bulk
dispersion while mixing. The active ingredient is gradually
dispersed in the bulk liquid while mixing continuously, to produce
a uniform dispersion. Flavorant and Colorant are added and the
volume is adjusted to 100 ml by addition of purified water. The
suspension is then homogenized by passing through a pump and a
colloid mill.
[0110] The foregoing Examples are illustrative of the present
invention and are not to be construed as limiting thereof. The
invention is defined by the following claims including equivalents
thereof.
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